14,15β-dihydroxyklaineanone inhibits HepG2 cell proliferation and migration through p38MAPK pathway.
Antineoplastic Agents, Phytogenic
/ isolation & purification
Apoptosis
/ drug effects
Carcinoma, Hepatocellular
/ drug therapy
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Diterpenes
/ isolation & purification
Down-Regulation
/ drug effects
Eurycoma
/ chemistry
Hep G2 Cells
Humans
Liver Neoplasms
/ drug therapy
MAP Kinase Signaling System
/ drug effects
S Phase Cell Cycle Checkpoints
/ drug effects
p38 Mitogen-Activated Protein Kinases
/ metabolism
14,15β-dihydroxyklaineanone
HepG2 cell
migration
p38MAPK
proliferation
Journal
The Journal of pharmacy and pharmacology
ISSN: 2042-7158
Titre abrégé: J Pharm Pharmacol
Pays: England
ID NLM: 0376363
Informations de publication
Date de publication:
Sep 2020
Sep 2020
Historique:
received:
23
12
2019
accepted:
21
04
2020
pubmed:
19
5
2020
medline:
29
5
2021
entrez:
19
5
2020
Statut:
ppublish
Résumé
Eurycoma longifolia Jack (Simaroubaceae) is commonly distributed in the Southeast Asia and Indo China, which has been shown to possess antianxiety, antibacterial, anticancer, antifungal, anti-inflammatory, antimalarial and antioxidant biological activities. 14,15β-dihydroxyklaineanone is a diterpene isolated from E. longifolia Jack, which is cytotoxic against human lung cancer and human breast cancer cell lines. However, the effects and underlying mechanisms of 14,15β-dihydroxyklaineanone on hepatocellular carcinoma remain unknown. Cell viability assay and colony formation assay were used to measure HepG2 cell proliferation. Flow cytometry was used to analyse cell cycle and apoptosis. Wound-healing assay and transwell assay were used to observe cells migration. RNA sequencing and the enrichment of differentially expressed genes (DEGs) in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were used to find and determine underlying pathways. We found that 14,15β-dihydroxyklaineanone inhibited the growth and migration of HepG2 cells but did not induce cell apoptosis. 14,15β-dihydroxyklaineanone induced S cell cycle arrest by downregulating the expression levels of cyclin A, p-CDK2, cyclin B1, p21, E2F-1 and PCNA. In addition, RNA sequencing showed that 14,15β-dihydroxyklaineanone regulated MAPK pathway by increasing the expression levels of phosphor-p38. Downregulating of p38 via both p38 inhibitor (SB203580) and p38-siRNA could antagonize the inhibition of cell proliferation and migration and reverse the changes in p-p38, E-cadherin, N-cadherin and PCNA expression induced by 14,15β-dihydroxyklaineanone treatment. 14,15β-dihydroxyklaineanone inhibited cell proliferation and migration through regulating p38 MAPK pathway in HCC cells.
Substances chimiques
Antineoplastic Agents, Phytogenic
0
Diterpenes
0
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1165-1175Subventions
Organisme : Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University)
ID : CMEMR2016-B05
Organisme : Innovation Project of Guangxi Graduate Education
ID : YCSW2019041
Organisme : the Project of Guangxi Collaborative Innovation Center in Guilin Medical University
Organisme : Guangxi Key Laboratory for Agro-Environment and Agro-Product Safety (Agriculture College, Guangxi University)
ID : 17-259-82
Organisme : Specific Research Project of Guangxi for Research Bases and Talents
ID : 18126005
Organisme : the Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology & Business University (BTBU)
Informations de copyright
© 2020 Royal Pharmaceutical Society.
Références
Zhou S et al. Nuclear factor-erythroid 2-related factor 3 (NRF3) is low expressed in colorectal cancer and its down-regulation promotes colorectal cancer malignance through activating EGFR and p38/MAPK. Am J Cancer Res 2019; 3: 511-528.
Bao H et al. Long non-coding RNA Igf2as controls hepatocellular carcinoma progression through the ERK/MAPK signaling pathway. Oncol Lett 2017; 3: 2831-2837.
Bhat R, Karim AA. Tongkat Ali (Eurycoma longifolia Jack): a review on its ethnobotany and pharmacological importance. Fitoterapia 2010; 7: 669-679.
Rehman SU et al. Review on a traditional herbal medicine, Eurycoma longifolia Jack (Tongkat Ali): its traditional uses, chemistry, evidence-based pharmacology and toxicology. Molecules 2016; 3: 331.
Kuo PC et al. Cytotoxic and antimalarial constituents from the roots of Eurycoma longifolia. Bioorg Med Chem 2004; 3: 537-544.
Fiaschetti G et al. Quassinoids: from traditional drugs to new cancer therapeutics. Curr Med Chem 2011; 3: 316-328.
Low BS et al. Standardized quassinoid-rich Eurycoma longifolia extract improved spermatogenesis and fertility in male rats via the hypothalamic-pituitary-gonadal axis. J Ethnopharmacol 2013; 3: 706-714.
Nguyen HD et al. 7-methoxy-(9H-beta-Carbolin-1-il)-(E)-1-propenoic acid, a beta-carboline alkaloid from Eurycoma longifolia, exhibits anti-inflammatory effects by activating the Nrf2/Heme oxygenase-1 pathway. J Cell Biochem 2016; 3: 659-670.
Tung NH et al. Quassinoids from the root of Eurycoma longifolia and their antiproliferative activity on human cancer cell lines. Pharmacogn Mag 2017; 51: 459-462.
Jiwajinda S et al. In vitro anti-tumor promoting and anti-parasitic activities of the quassinoids from Eurycoma longifolia, a medicinal plant in Southeast Asia. J Ethnopharmacol 2002; 1: 55-58.
Meng D et al. Four new quassinoids from the roots of Eurycoma longifolia Jack. Fitoterapia 2014; 92: 105-110.
Tran TV et al. NF-kappaB inhibitors from Eurycoma longifolia. J Nat Prod 2014; 3: 483-488.
Wang CK et al. Inhibition of growth and motility of human A549 lung carcinoma cells by a recombined vascular basement membrane derived peptide. Cancer Lett 2010; 2: 261-268.
Moldovan GL et al. PCNA, the maestro of the replication fork. Cell 2007; 4: 665-679.
Bartova E et al. PCNA is recruited to irradiated chromatin in late S-phase and is most pronounced in G2 phase of the cell cycle. Protoplasma 2017; 5: 2035-2043.
Xiong Y et al. p21 is a universal inhibitor of cyclin kinases. Nature 1993; 6456: 701-704.
Hayashi A et al. PCNA-dependent ubiquitination of Cdt1 and p21 in mammalian cells. Methods Mol Biol 2014; 1170: 367-382.
Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci 2005; 11: 630-641.
Lamouille S et al. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 3: 178-196.
Markopoulos GS et al. Epigenetic regulation of inflammatory cytokine-induced epithelial-to-mesenchymal cell transition and cancer stem cell generation. Cells 2019; 8: 1143.
Aleskandarany MA et al. Epithelial mesenchymal transition in early invasive breast cancer: an immunohistochemical and reverse phase protein array study. Breast Cancer Res Treat 2014; 2: 339-348.
Miyamoto Y et al. N-cadherin-based adherens junction regulates the maintenance, proliferation, and differentiation of neural progenitor cells during development. Cell Adh Migr 2015; 3: 183-192.
Munshi A, Ramesh R. Mitogen-activated protein kinases and their role in radiation response. Genes Cancer 2013; 9-10: 401-408.
Huynh H et al. Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol 2003; 3: 19.
Guichard C et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 2012; 6: 694-698.
Chen J et al. Human mesenchymal stem cells promote tumor growth via MAPK pathway and metastasis by epithelial mesenchymal transition and integrin alpha5 in hepatocellular carcinoma. Cell Death Dis 2019; 6: 425.
Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J 2010; 3: 403-417.
Zou X, Blank M. Targeting p38 MAP kinase signaling in cancer through post-translational modifications. Cancer Lett 2017; 384: 19-26.
Manke IA et al. MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell 2005; 1: 37-48.
Molnar A et al. Cdc42Hs, but not Rac1, inhibits serum-stimulated cell cycle progression at G1/S through a mechanism requiring p38/RK. J Biol Chem 1997; 20: 13229-13235.
Takenaka K et al. Activation of the protein kinase p38 in the spindle assembly checkpoint and mitotic arrest. Science 1998; 5363: 599-602.
Hernandez Losa J et al. Role of the p38 MAPK pathway in cisplatin-based therapy. Oncogene 2003; 26: 3998-4006.